Process for the preparation of delta9(11)-steroid compounds



United States Patent 3,275,665 PROCESS FOR THE PREPARATION OF M -STEROIDCOMPOUNDS Peter Ziegler, Toronto, Ontario, and John C. Grivas, Weston,Ontario, Canada, assignors to Canada Packers Limited, Toronto, Ontario,Canada No Drawing. Filed Jan. 23, 1964, Ser. No. 339,611 19 Claims. (Cl.260-3975) This invention relates to a novel process for the preparationof M -steroid compounds from 12-oxygenated steroid starting materialsand, in particular, to a process for the conversion of 12-oxygenatedsteroids, such as those occurring in the bile acids and sapogenins andderivatives thereof, into M -steroid compounds devoid of the C12 oxygenfunction.

The M -steroid compounds produced by the present process are importantintermediates for the preparation of ll-oxygenated steroid hormonesincluding cortisone, hydrocortisone and the derivatives and analoguesthereof, and particularly, for the preparation of corticosteroids ofhigh therapeutic value which are characterized by an oxygen function atposition 11 and another substituent such as halogen, at position 9.

It is well known in the art that one of the main difiiculties in themanufacture of corticoid hormones is the introduction of an oxygenfunction at 0-11 of the cyclopentanophenanthrene molecule. Thisoperation is still more difiicult if it is also desired to introduce ahalogen atom at position C9, particularly when using as startingmaterials compounds containing a keto group at position C12. The usualprocedure has involved initial production of the ll-oxygenated steroidsby one of the lengthy routes known to the art. The 9,1l-disubstitutedsteroids are then prepared in rather unsatisfactory yield, from therelatively expensive ll-oxygenated steroids by a series of complexreaction steps, e.g., involving tosylation ofthe ll-oxy group,dehydrotosylation to provide the 9( ll) double bond, and addition ofhypohalous acid to the M -bond. Transformation of M -compounds to the9m-halo-11B-hydroxy derivatives is described in Patent No. 2,852,511.

The present invention permits the important A -in termediates to beproduced in good yields from the 12- oxygenated steroid startingmaterials without going through the ll-oxygenated compounds and withrelatively few process steps. We have discovered that the 12-oxygenfunction can be eliminated from A -12-keto and A -IZ-hydroxysteroids ina very satisfactory manner by reduction with alkali metal aluminumhydride-aluminum halide reagent. Substantially pure M -compounds freefrom A -isomers, are readily recovered from the reaction mixture in goodyields. This is quite surprising in view of the difiiculties that havebeen encountered with other methods.

The Wolff-Kishner reduction or its Huang-Minlon modification representsa standard method for the reduction of carbonyl functions to methyl ormethylene groups. Excellent yields are obtained in the case of isolated,nonconjugated ketones. Even hindered saturated ketones can be reduced bythis procedure. However, conjugated carbonyl groups behave somewhatdifferently, sometimes forming cyclic compounds or involving a 1,2-shiftof the double bond. Several workers have applied the Wolff- Kishnerreduction to A -l2-ketosteroids. Reichstein reduced A -12-ketocholenicacid as well as the corresponding S-hydroxy analogue and obtained amixture of A and A -cho1enic acids which could not be separated bystandard methods even though it seems that the M -isomer predominates.On the other hand, application of the Huang-Minlon procedure tosapogenins gave relatively satisfactory results; A -dehydrotigogenin was1 obtained in somewhat better than 50% yield from the corresponding12-keto compound. The difference in the behavior of the bile acids andsapogenins is apparently due to the fact that the M -unsaturatedcompound crystallizes out very readily from the mixture of A and A-s-apogenins, while the A and A -unsaturated bile acid mixtures areisomorphic. This difficulty in separation of isomers with compounds ofthe bile acid series is not encountered when the reduction is carriedout by the process of the present invention.

It will be seen that the present invention is of particular advantage inpreparing the M -steroid compounds from the corresponding 12-oxygenatedsteroids in the bile acid series. Another advantage consists in the factthat A 12-ketosteroid starting materials are readily available in goodyield from the bile acids by known methods. Thus, methyl 3a-acetoxy-A-l2-ke'tocholenate or its saponification product can be obtained inapproximately yield from desoxycholic acid by conversion of the acid tomethyl 3a-acetoxy-l2-ketochloanate followed by treatment with seleniumdioxide. It will be understood, however, that the alkali metal aluminumhydride-aluminum halide reduction can also be utilized with A -12-ketoand A -l2-hydroxysteroid starting materials from other sources.

Therefore, it is an object of the present invention to provide animproved process for the preparation of A steroid compounds from steroidstarting materials having a 12-oxygen function.

Another object of the present invention is to provide an improved methodfor removing the 12-oxygen function from M -unsaturated 12-oxygenatedsteroid compounds.

A further object of the invention is to provide an improved process forremoving the 12-oxygen function from 12-oxygenated M -steroid compoundshaving the bile acid side chain so as to improve the economics of thebile acid route to cortical steroids.

Another still further object of the invention is to provide an improvedprocess for the conversion of l2-ketopregnane compounds to useful M-derivatives.

The invention in one aspect comprises the reduction of either A -12-ketoor A -12-hydroxysteroids by treatment with alkali metal aluminumhydride-aluminum halide reagent to eliminate the l2-oxygen function.This is essentially a one-step direct reduction method. An additionalfeature of the invention resides in a two-stage reduction method for12-keto-A -steroids wherein the l2-keto group is first reduced toIZE-hydroxy with a mild reducing agent, such as alkali metalborohydride, and the 1 IZzZ-hydroxy group is then eliminated bytreatment with the alkali metal aluminum hydride-aluminum halidereagent. Lithium aluminum hydride-aluminum chloride reagent is thepreferred alkali metal aluminum hydride-alkali metal halide reagent andsodium borohydride is the preferred reducing agent for the preliminaryreducing step of the two-stage operation. Though the two-stage reductionresults in somewhat greater yields, the direct reduction is ofcomparable commercial significance because of i the obvious advantagesin a single-stage process obviating the necessity of separating theintermediate and the further reaction with additional reagents.

The process of the invention, as aforestated, has general application toA -12-keto and A -l2-hydroxysteroids and may be applied, for example, toderivatives of ergostane, cholestane, coprostane, sitostane,stigmastane, spirostane, cholane, allocholane, pregnane, allopregnane,and androstane. The starting materials can be variously substituted inthe nucleus or in the side chain and can have any configuration. Ketoand ester groups,

if present in other positions on the steroid nucleus, e.g.,

at C3, in general, are converted to hydroxyl during the course of theLiAlIh-AlCl reduction. Hydroxy or acetoxy groups in the C17 side chain,particularly at the C20 position seem to hinder the attack on the C-12oxygen function and preferably are removed prior to the LiAlH AlClreduction. Free acid or esterified acid groups in the side chain, e.g.,at -21 or C-24 are reduced to corresponding alcohols.

A representative series of reactions starting with desoxycholic acid andutilizing the procedure of the present invention is as follows:

m coon LiAlHt R0 A1013 fi CHzOR I H0 In the foregoing representationdesoxycholic acid (1) is converted into methyl3u-acetoxy-l2-ketocholanate (2).

by known procedures, e.g., by methylating the acid, acetylating theresulting methyl desoxycholate to provide methyl3u-acetoxy-12ot-hydroxycholanate, and oxidizing this compound withchromic acid. Good yields of methyl 3ot-acetoxy-12-ketocholanate areobtainable. This compound (2) is then subjected to selenium dioxidetreatment, preferably in acetic acid, so as to obtain the 12- keto-A-compound (3). In compound (3) R may be hydrogen or alkyl (e.g., methyl)and R may be hydrogen or Ac, where Ac is the acyl radical of ahydrocarbon carboxylic acid containing from 1 to 12 carbon atoms (e.g.,acetyl). The conversion of (3) to (4) is shown as a one-step reductionwith LiAlH AlCl but this may alternatively be accomplished by thetwo-stage operation described above.

Further graphical illustrations representing the invention are asfollows:

Lnurn- I A1013 R1" HO (I) (III) (B) O R:

C NaBI-I;

( 2H R 4 R5 Oj lia. I

R HO

(II) (III) wherein R is OAc, OH or tO-COOEt;

R2 is 0 H3 CH3 Where Ac is the same as defined above.

The reduction-removal of the 12-keto or l2-hydroxyl group with alkalimetal aluminum hydride in the pres spect to the steroid, of lithiumaluminum hydride and aluminum chloride reagent prepared in ether.Caution should be exercised in the preparation and handling of the LiAlHAlCl reagent. All the equipment, reagents and solvents should be driedand the reaction carried out under anhydrous conditions. Preferably,AlCl is first added to the ether and then the LiAlI-L; is slowly addedto the ethereal solution of A101 since considerable heat is produced.The same consideration should be applied during addition of the steroidsolution to the reagent and during the decomposition of the reactionmixture with water and dilute acid.

It is usually preferable to freshly prepare the LiAlH AlCl reagent andthen the solution of steroid is slowly added to this reagent within ashort time after preparation, preferably within 5 to 10 minutes. Afterthe steroid solution has been added to the reagent, the hydrogenolysisof the steroid compound is completed by refluxing for a suitable period,for example, for about 2 to 5 hours. The reaction mixture is then cooledto room temperature whereupon addition of water and acid decomposesexcess reducing agent and acidifies the product.

Lower temperatures and longer reaction times may be used withsatisfactory results. Hydrogenolysis will proceed at room temperatureovernight.

Any non-crystalline residue from this reaction, on additional reductionwith the reducing reagent, can provide substantial additional amounts ofM -compound.

Ethers generally are the best solvents for this reaction. The loweralkyl ethers such as ethyl ether have been found to give better resultsthan ethers such as tetrahydrofuran (THF) or dioxane, although either ofthe latter may be used.

A molar excess of LiAlI-L, reducing agent with respect to steroid shouldbe employed but the amount of the excess is not sharply critical.However, in order to obtain maximum yields of the N -steroid product inreadily recoverable form, proper proportions of AlCl to LiAlH must beutilized. It has been found that a ratio of AlCl to LiAlH of between 1:1to 4:1 provides satisfactory results with best results being obtainedwith a ratio between 2:1 and 4:1. Below 1:1 relatively low yields ofdifiicultly separable product are obtained. Above 4:1 appears to provideno advantage. This is illustrated by experiments which are summarized inthe following table:

1 Methyl 3a,12E-dihydroxy-A" -cholenate.

2 312,2LdihYdtXY-A (11) -cholene.

3 Yield after retreatment of the residue obtained from first treatment.

4 Product had broad melting range and contained chlorine.

Product again contained chlorine, had a broad melting range and purity,could not be improved by repeated recrystallization.

The two-step process, represented by Equation B above, consists oftreatment of type I compounds with a mild reducing agent such as sodiumborohydride to effect reduction of the 12-keto function to the12-hydroxy function. The procedure of US. Patent 2,862,933 may be used.Usually, this reaction produces a mixture of the two possible 12-hydroxyisomers, this mixture being designated as type II compounds. Thismixture of isomers is then used in the second step (afteresterification, if desired) or the mixture of isomers may be separatedinto its two components (12w and 12,8- hydroxy compounds) prior to thesecond step. It has been found that esterification of type II compoundshaving the bile acid side chain, prior to the second step, in mostinstances results in improved yields. The 12a-hydroxy isomer is reducedmore rapidly and in greater yields than the IZfi-hydroxy isomer.However, separation of these isomers is not essential. The product ofthe first reaction (type II compounds) is then treated with LiAlH AlClto produce compound of type III.

Reduction of the A -ketosteroids of type I with excess sodiumborohydride proceeds substantially quantitatively in aqueous alkalinesolution at about 20 C. to 25 C. for 20 hours and in shorter time atelevated temperature. The reaction can also be carried out in refluxingaqueous tetrahydrofuran in about 3 to 4 hours, but the yield is lesssatisfactory, e.g., about 7080%. Ester groups on the bile acid sidechain or acyloxy groups at C-3 are not affected by this reduction. The

excess reducing agent is decomposed and the product precipitates on theaddition of dilute sulfuric acid. The precipitate can be washed anddried or extracted with ether, washing the extracts, drying andevaporating to give a residue of the desired product. The intermediate,if in acid form (R of II has a free acid group hydrogen) can be useddirectly for the second reduction step or may first be methylated bydissolution in methanol and reaction with an ethereal solution ofdiazomethane. The solvents are then evaporated to give the crude ester(R of II has an esterified acid group).

The crude acid or ester (type II) is then dissolved in ether and thissolution is added dropwise to a stirred solution of AlCl LiAlH in ether.Hydrogenolysis of the steroid proceeds by refluxing for about 4 hourswhereupon the 12-hydroxy group is removed with the simultaneousreduction of the side chain acid or ester groups to 24-hydroxy and theaccompanying reduction of the 3-acyloxy group, if present. The mixtureis then cooled, decomposed by dropwise addition of water, acidified withdilute H and extracted with ether. The solvent extract is washed withwater, dried and evaporated to provide the desired A compound of typeIII. The compound in substantially pure form can be obtained bycrystallization from ether. On evaporating the ether to dryness afterremoval of crystalline material, a noncrystalline residue is obtainedwhich on retreatment with AlCl LiAlH affords additional amounts of IIIproviding total yields of up to 80% or more.

The following specific examples are illustrative of the invention.

Example 1.-Preparali0n of 3a,24-d[hydroxy-A clzolene from methyl3a-acet0xy-A -ZZ-ketocholenate 4.5 hours, cooled to 20 C., anddecomposed by dropwise addition of water and dilute sulfuric acid. Theether layer was separated, the aqueous layer was extracted withmethylene chloride, the two solvent extracts were combined, washed withwater, dried over magnesium sulfate, and evaporated to dryness. Theresidue (1.94 g.) was taken up in ether, the mixture was refrigerated,and the precipitate was filtered oil to provide 1.14 g. (60%) of3a,24dihydroxy-A -cholene, M.P. 177 C.

Recrystallization from methylene chloride-ether :af-

forded pure 3a,24-dihydroxy-A -cholene, M.P. 178- 180 C. and [041 +55.6(c., 0.488, dioxane).

Example 2.Preparation of 3a,24-dihydr0xy-A cholene from Sa-hydroxy-A-IZ-ketocholenic acid 3ot-hydroxy-A -12-ketocholenic acid 10 g.) wasdissolved in a solution of sodium hydroxide (1.15 g.) in distilled water(50 ml.). Sodium borohydride (2.5 g.) was added, the mixture was stirredat 20 C. for 20 hours, and the clear solution was then added dropwise toa stirred solution of concentrated sulfuric acid (3.6 ml.) in water (100ml.). The resulting precipitate was filtered off, washed with water, andvacuum-dried at 60 C. to give 9.96 g. of crude 3a,125-dihydroxy-A-cholenic acid as a white solid.

The above crude acid (3 g.), dissolved in methanol, was methylated withan ethereal solution of diazomethane. The solvents were evaporated invacuo to give methyl 3a,l25-dihydroxy-A -cholenate (3.12 g.).

The crude methyl ester (2.29 g.) was dissolved in other (100 ml.), andthis solution was then added dropwise to stirred lithium aluminumhydride-aluminum chloride reagent in ether. The latter was prepared bydissolving aluminum chloride (6.05 g.) in ether (50 ml.), slowly addingthereto lithium aluminum hydride (1.07 g.), and stirring at 20 C. for 20minutes. The hydrogenolysis of the steroid was carried out by refluxingthe mixture for 4 hours. The mixture was cooled, decomposed by dropwiseaddition of water, acidified with dilute H 50 and extracted with ether.The solvent extract was washed with water, dried, and evaporated to asmall volume to provide 1.22 g. of 3a,24-dihydroxy-A -cholene, M.P.172-l75 C. The filtrate was evaporated to dryness, the residue wasre-treated as above to afford an additional 0.25 g. of the product, M.P.l72175 C. Total yield was 1.47 g. (72%).

Example 3.-Preparatin 0f 3a,24-dihydroxy-A cholene from methyl3a-acet0xy-A -12-ket0ch0lenate Methyl 3a-acetoxy-A -12-ketocholenate(4.45 g.) was dissolved in tetrahydrofuran (50 rnl.), a solution ofsodium borohydride (0.76 g.) in water (3 ml.) was added, and the mixturewas refluxed for 3-4 hours. The mixture was cooled, carefully decomposedby dilute sulfuric acid, and the products were extracted twice withether. The combined solvent extracts were washed with water, dried, andevaporated to give a residue (4.54 g.), containing mixed 1211- andIZfi-hydroxy isomers of methyl 3a-acetoxy-A -cholenate.

This residue (4.54 g.) was dissolved in ether (80 1111.), and thesolution was then added dropwise over a period of half an hour to theethereal solution (80 ml.) of the lithium aluminum hydride-aluminumchloride reagent. The latter was prepared from aluminum chloride (10.5g.; 0.08 mole) and lithium aluminum hydride 1.9 g.; 0.05 mole) in themanner described in previous examples. The reaction mixture was refluxedfor 4.5 hours, it was then worked up in the usual fashion to yield aresidue (3.7 g.) which crystallized from ether to give 1.51 g. of3a,24-dihydroxy-A -cholene, M.P. 174-177 C. A second crop yielded anadditional 0.283 g. of the product. Evaporation of the ether andretreatment of the residue resulted in an additional 0.223 g. ofproduct. Total yield 56%.

Example 4.Preparati0n of 3a,24-dihydr0xy-A cholene from3a,12-dihydr0xy-A -cholenic acid 30:,12g-dihydroxy-A -cholenic acid(0.95 g.), prepared according to the procedure of Example 2, was putinto a Soxhlet extraction thimble. LiAlH AlCl reagent was prepared inether (150 ml.) from AlCl (5.25 g.) and LiAlH (0.95 g.). The reagentsolution was then refluxed for 9 hours in the Soxhlet apparatus, andduring this time, the condensed ether gradually dissolved all of thesteroid in the extraction thimble. The mixture was treated in the usualfashion, and the product was isolated by crystallization from ether toyield 0.429 g. (55%) of 3a,24-dihydroxy-A -cholene, M.P. 173-176 C.

Example 5.Preparati0n of 3oc,24-dihydr0xy-A F -ch0- lene from methyl3a,12a-dihydr0xy-A -ch0lenate and from methyl 3a,12,8-dihydr0xy-A-cholenate Example 6.-Preparation of 3a-hydroxy-A pregnene from3ot-eth0xycarb0rzyl0xy-A Q -IZ-ketOpregnene One gram of3a-ethoxycarbonyloxy-A -12-ketopregnene [prepared from3a,12a-dihydroxypregnane-20= one by reducing this compound to3a,12ot-dihydroxypregname by Huang-Minlons modification of the Wolff:Kishner reduction, preferential esterification of this compound to givethe Ba-cathylate (3a-ethoxycarbonyloxy- 12a-hydroxypregnane), oxidationof the mono-cathylate with chromic acid to convert the 12-hydroxy groupto 12- keto, and dehydrogenation of the3a-ethoxycarbonyloxyl2-ketopregnane with selenium dioxide to provide Aunsaturation], dissolved in tetrahydrofuran (20 ml.), was treated with asolution of NaBH (0.3 g.) in Water (1.5 ml.), and the mixture Wasrefluxed for 5 hours. After a decomposition with dilute sulfuric acid,the products were extracted with ether, and the solvent extract wasprocessed in the usual manner to yield an amorphous residue (0.97 g.).

AlCl (5.5 g.; 41 mmole) was dissolved in ether (30 1111.), then LiAlH(0.49 g.; 12.5 mmole) was added in portions, and the mixture was stirredfor 20 minutes. A solution of the steroid (0.97 g.; 2.5 mmole) in ether(30 ml.) was then added dropwise within 15 minutes, and the mixture wasrefluxed for 4 hours. Decomposition by water, then by dilute sulfuricacid was followed by extraction with ether. The solvent extract waswashed, dried, and evaporated to provide a residue (0. g.) from which580 mg. (75%) of 3ot-hydroxy-A -pregnene" were isolated. This materialhad double M.P. 121-122 C. and 128129 C.

The foregoing examples show that lithium aluminum hydride-aluminumchloride reagent in proper proportions effectively eliminates the12-hydroxy group from methyl 30c l2 dihydroxy-A -cholenate, methyl306-2lCtOXy- A -12-hydroxycholenate and from 3u,12-dihydroxy- A-cholenic acid, the compounds being present either as a mixture of thelZuand 12,8-hydroxy isomers or in the form of a single isomer. The samereaction is also shown to be applicable to the t e-unsaturated ketonessuch as methyl 3wacetoxy-M -l2-ketocholenate to yield the desired M-steroid. Additionally, it has been illustrated that the reaction iseffective in the pregnane series. applicability and that an importantand new link in the production of M -intermediates has been provided.

, We claim:

1. A process which comprises reacting a 12-oxygenated-A -steroidcompound in which any C 2O carbon atom present is bonded only to carbonand hydrogen atoms with an alkali metal aluminum hydride-aluminum halidereducing agent to remove the l2-oxygen function.

2. The process of claim 1 wherein the 12-oxygenated- M -steroid compoundreacting with said reducing agent has a 12-keto group.

3. The process of claim 1 wherein the 12-oxygenated- M -steroid compoundreacting with said reducing agent has a 12-hydroxy group.

4. A process as claimed in claim 1 in which the reducing agent comprisesan ethereal solution of aluminum chloride and lithium aluminum hydridein a molar ratio of AlCl to LiAlH greater than unity.

5. A process as claimed in claim 4 in which the ratio of AlCl to LiAlHis from about 2:1 to 4:1.

6. A process which comprises the steps of reducing a A -l2-ketosteroidcompound in which any C-20 carbon atom present is bonded only to carbonand hydrogen atoms with a mild reducing agent to convert the 12-ketogroup to a 12-hydroxy group and then reacting the resulting A-l2-hydroxysteroid compound with an alkali metal aluminumhydride-aluminum halide reducing agent to remove the l2-hydroxy group.

7. A process as claimed in claim 6 in which the mild reducing agent isan alkali metal borohydride and the It is apparent that the inventionhas widespread second reducing agent is aluminum chloride-lithiumaluminum hydride in a molar ratio of AlCl to LiAlH greater than unity.

A process as claimed in claim 7 in which the mild reducing agentcomprises NaBH and the molar ratio of AlCl to LiAlH is from about 2:1 to4:1.

9. A process as claimed in claim 8 in which the reduction of the 12-ketogroup to a 12-hydroxy group is conducted With an excess of sodiumborohydride in aqueous alkaline solution.

10. A process comprising reacting a l2-oxygenated- M -steroid compoundof the bile acid series with an excess of AlCl LiAlH to remove the12-oxygen function.

11. A process for preparing 3a,24-dihydroxy-A cholene comprisingreacting an alkyl 3a-acy1oxy-A 12-ketocholenate with an excess of AlClLiAlH to remove the 12-keto group with accompanying reduction of the3o-acyloxy group and reduction of the alkyl ester group in the sidechain.

12. A process for preparing 3a,24-dihydroxy-A cholene comprisingreducing 3a-hydroxy-A -12-ketocholenic acid with sodium borohydride toprovide the l2-hydroxy derivative thereof and reacting said l2-hydroxyderivative with an excess of AlCl -LiAlH to remove said 12-hydroxy groupwith simultaneous reduction of the 24-carboxyl group.

13. A process as claimed in claim 12 in which the acid is esterifiedprior to reaction with AlCl LiAlH and wherein removal of the l2-hydroxygroup is accompanied by reduction of the ester group.

14. A process for preparing 3a,24-dihydroxy-A cholene comprisingreducing an alkyl 3-acyloxyA 12-ketocholenate with sodium borohydride toprovide the corresponding 12-hydroxy derivative thereof and reactingsaid 12-hydroxy derivative with an excess of AlCl LiAlH to remove said12-hydroxy group with accompanying reduction of the S-acyloxy group andreduction of the alkyl ester group.

15. A process for preparing 3a,24-dihydroxy-A cholene comprisingreducing a compound selected from the group consisting of 3a--hydroxy-A12-ketocholenic acid, alkyl esters and esterified 30t-dflVatlV6Sthereof, with a mild reducing agent to provide a mixture of thecorresponding l2u-hydroxy and 12fi-hydroxy isomers, separating saidisomers and subjecting the 12a-hydroxy isomer to reduction with AlClLiAlH to remove the 12-hydroxy group.

16. A process for preparing 3a,24-dihydroxy-A cholene from desoxycholicacid comprising converting said desoxycholic acid to a compound selectedfrom the group consisting of 3a-hydroxy-iA -12-ketocholenic acid, alkylesters and esterified BOC-dEI'lVHtlVfiS thereof, by steps includingchromic acid oxidation of the 12- hydroxy group and selenium dioxidedehydrogenation of the resulting 12-ketosteroid to provide M-unsaturation, and then subjecting the resulting 12-keto-A steroidcompound selected from said group to reduction to remove the 12-oxygenfunction, said reduction including treatment with AlC1 LiAlH 17. Theprocess of claim 16 wherein said reduction is accomplished by directreduction of the 12-keto-A steroid compound with AlCl LiAlH 18. Theprocess of claim 16 wherein said reduction is accomplished by treatmentof said 12-keto-A steroid compound with NaBH., to reduce the 12-ketogroup to a 12-hydroxy group and the resulting 12-hydroxy compound isthen reduced with the AlCl -LiAlH to remove the 12-hydroxy group.

19. A process for the preparation of 3a-hydroxy-A pregnene comprisingreacting 3a-ethoxycarbonyloxy- A -12-ketopregnene with sodiumborohydride to provide the IZ-hydroxy derivative of said steroid andreacting said derivative with an excess of AlCl -LiAlH to remove said12-hydroxy group with accompanying reduction of the 3-ethoxycarbonyloxygroup.

References Cited by the Examiner UNITED STATES PATENTS 12/1958 Smit etal. 260-397.1

OTHER REFERENCES LEWIS GOTTS, Primary Examiner.

T. M. MESHBESHER, Assistant Examiner.

1. A PROCESS WHICH COMPRISES REACTING A 12-OXYGENATED-$9(11)-STEROIDCOMPOUND IN WHICH ANY C-20 CARBON ATOM PRESENT IS BONDED ONLY TO CARBONAND HYDROGEN ATOMS WITH AN ALKALI METAL ALUMINUM HYDRIDE-ALUMINUM HALIDEREDUCING AGENT TO REMOVE THE 12-OXYGEN FUNCTION.
 12. A PROCESS FORPREPARING 3A,24-DIHYDROXY-$9(11)CHOLENE COMPRISING REDUCING3A,-HYDROXY-$9(11)-12-LETOCHOLENIC ACID WITH SODIUM BOROHYDRIDE TOPROVIDE THE 12-HYDROXY DERIVATIVE THEREOF AND REACTING SAID 12-HYDROXYDERIVATIVE WITH AN EXCESS OF ALCO2-LIALH4 TO REMOVE SAID 12-HYDROXYGROUP WITH SIMULTANEOUS REDUCTION OF THE 24-CARBOXYL GROUP.